Administrative Supplement to 7R01HL148060-03 Titled: Opposing Effects of Prostaglandin E2 EP3 and EP4 Receptors on Mitochondrial

7R01HL148060-03 的行政补充，标题为：前列腺素 E2 EP3 和 EP4 受体对线粒体的相反作用

基本信息

批准号：
10711712
负责人：
PAMELA HARDING
金额：
$ 7.7万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-15 至 2024-01-31
项目状态：
已结题

项目摘要

ABSTRACT Heart disease and heart failure are important causes of morbidity and mortality, affecting approximately 300 million people, at an enormous cost. Although current treatments slow the progression of these diseases, there has been little progress in preventing the compensated heart transitioning to that of a failing one. The Prostaglandin E2 (PGE2) receptor subtypes EP3 and EP4 are most abundant in the heart and activate different signaling pathways (Gαi for EP3, Gαs for EP4). Compelling data from my laboratory shows that EP3 expression is increased in the pathologically diseased heart produced by myocardial infarction (MI) or Angiotensin II- dependent hypertension (Ang II-HTN), that stimulation of the EP3 receptor decreases cardiac contractility whereas EP4 increases it and that overexpression of EP4 in the failing heart improves cardiac function. The failing heart switches from fatty acid (FA) oxidation to reliance on glucose. Coupled with this are alterations in mitochondrial function. Thus, mitochondrial dysfunction is an important player in the pathogenesis of heart failure. Our previous gene array data showed dramatic down regulation of mitochondrial genes in mice in which the EP4 receptor was deleted in cardiomyocytes; allowing PGE2 to act via the EP3 receptor and new data shows that an EP3 agonist reduces Complex I activity and ATP levels in adult mouse cardiomyocytes. mRNAs for proteins that alter both FA oxidation and their transport into mitochondria; specifically, carnitine palmitoyl transferase (CPT) were also down regulated in EP4 KO hearts. In other tissues, CPT activity was reportedly regulated by the transcription factor/orphan receptor NR4A2 (Nurr1) in a PGE2-dependent process but whether this occurs in the heart is unstudied. Since heart failure is characterized by reduced FA oxidation, we propose the novel overall hypothesis: EP3 is increased during cardiac injury and impairs mitochondrial function due to reduced fatty acid import via diminished CPT activity. This is mediated by decreased activity of the transcription factor, NR4A2. Ultimately these events contribute to heart failure. To test this hypothesis, we propose 3 aims that will use a new conditional and cardiomyocyte-specific EP3 KO mouse model coupled with an EP3 overexpressing transgenic mouse to determine whether upregulation of cardiomyocyte EP3 contributes to impaired contractile function and reduced mitochondrial function in heart failure caused by Ang II-HTN and MI. The study also examines whether PGE2 via its EP3 receptor reduces import of fatty acids into mitochondria via decreased activity of the transcription factor NR4A2 which subsequently reduces CPT activity; and whether these events reduce subsequent ATP levels. The proposal employs a multidisciplinary approach including physiological, biochemical and imaging studies that will impact the treatment of heart failure.

抽象的心脏病和心力衰竭是发病率和死亡率的重要原因，影响约 300 人尽管目前的治疗方法减缓了这些疾病的进展，但仍花费了巨大的代价。在防止代偿心脏转变为衰竭心脏方面进展甚微。前列腺素 E2 (PGE2) 受体亚型 EP3 和 EP4 在心脏中最丰富，可激活不同的我的实验室的令人信服的数据表明 EP3 表达。因心肌梗塞 (MI) 或血管紧张素 II 引起的病理性病变心脏中的血管紧张素 II 含量增加依赖性高血压 (Ang II-HTN)，刺激 EP3 受体会降低心肌收缩力而 EP4 会增加它，并且 EP4 在衰竭心脏中的过度表达会改善心脏功能。衰竭的心脏从脂肪酸（FA）氧化转变为依赖葡萄糖。因此，线粒体功能障碍在心脏的发病机制中起着重要作用。我们之前的基因阵列数据显示，小鼠中线粒体基因的显着下调。心肌细胞中的 EP4 受体被删除；允许 PGE2 通过 EP3 受体发挥作用，新数据显示 EP3 激动剂复合物可降低成年小鼠心肌细胞 mRNA 的 I 活性和 ATP 水平。对于改变 FA 氧化及其转运到线粒体的蛋白质，特别是肉碱棕榈酰；据报道，EP4 KO 心脏中的转移酶 (CPT) 活性也下调。在 PGE2 依赖性过程中受转录因子/孤儿受体 NR4A2 (Nurr1) 调节，但是否这种发生在心脏中的现象尚未得到研究，因为心力衰竭的特点是 FA 氧化减少。新的总体假设：EP3 在心脏损伤期间增加，并由于以下原因损害线粒体功能通过降低 CPT 活性来减少脂肪酸输入这是由转录活性降低介导的。 NR4A2 因素最终会导致心力衰竭。为了检验这一假设，我们提出了 3 个目标。将使用新的条件性心肌细胞特异性 EP3 KO 小鼠模型以及 EP3 过表达转基因小鼠以确定心肌细胞 EP3 的上调是否有助于 Ang II-HTN 和 MI 引起的心力衰竭中收缩功能受损和线粒体功能降低。该研究还检验了 PGE2 是否通过其 EP3 受体减少脂肪酸进入线粒体通过转录因子 NR4A2 的活性降低，从而降低 CPT 活性；以及这些事件会降低随后的 ATP 水平。该提案采用了多学科方法，包括生理、生化和影像学研究将影响心力衰竭的治疗。